Male Hormonal Contraception and Metabolic Health

项目总结（见说明）： 全球人口继续以惊人的速度增长。调查表明，男女都希望有更多的男性避孕选择。男性激素避孕方案，包括雄激素加一个residestin是有吸引力的，因为它们具有高效率，是完全可逆的，并且，在新的男性避孕药，是最先进的临床开发。然而，人们担心男性外源性激素给药的性腺外效应，特别是心血管疾病（CVD）的长期风险。关于雄激素和孕激素对CVD危险因素影响的数据是混合的。一方面，男性激素避孕药降低了高密度脂蛋白（HDL），一种保护心脏的脂蛋白，并可能导致体重增加，随着时间的推移可能会增加胰岛素抵抗。相反，低水平的血清睾酮与CVD、胰岛素抵抗和死亡率的风险升高相关，这对外源性雄激素必然以剂量依赖性方式增加CVD风险的观点提出了质疑。本提案的总体目标是阐明男性激素避孕药对体内CVD三个重要风险因素的影响。我们将关注雄激素和孕激素对1）HDL介导的胆固醇流出（HDL的关键心脏保护功能），2）HDL相关蛋白组成和3）脂肪组织炎症（胰岛素抵抗的关键介导因子）的影响。新出现的数据暗示这些在CVD的发病机制中的每一个，并且每一个都可能被外源性类固醇修饰。 我们将在健康男性中进行一项安慰剂对照试验，以直接量化单独增加血清睾酮水平或联合收割机与有效的避孕药炔雌醇、醋酸去甲羟孕酮（DMPA）联合增加血清睾酮水平对人体HDL和脂肪组织的影响。为了补充我们的人类研究，我们将使用转基因小鼠来确定雄激素是否通过对脂肪组织巨噬细胞的影响来降低CVD风险，脂肪组织巨噬细胞是一种协调脂肪组织炎症和胰岛素抵抗的中心细胞类型。拟议的研究将提供关于雄激素和孕激素对男性代谢和CVD风险影响的临床和机制数据。

PROJECT SUMMARY (See Instructions): Global population continues to grow at an astonishing rate. Surveys suggest that both genders desire more male contraceptive options. Male hormonal contraceptive regimens that consist of androgens plus a progestin are attractive as they have high efficacy rates, are fully reversible, and, among novel male contraceptives, are the most advanced in clinical development. There are concerns, however, regarding the extra-gonadal effects of exogenous hormone administration in men, particularly surrounding long-term risk for cardiovascular disease (CVD). Data regarding the impact of androgens and progestins on risk factors for CVD are mixed. On the one hand, male hormonal contraceptives lower high-density lipoprotein (HDL), a cardioprotective lipoprotein, and can cause weight gain that might increase insulin resistance over time. In contrast, low levels of serum testosterone are associated with elevated risk for CVD, insulin resistance, and mortality, calling into question the notion that exogenous androgens necessarily increase CVD risk in a dose dependent manner. The overall objective of this proposal is to clarify the impact of male hormonal contraceptives on three important risk factors for CVD in vivo. We will focus on the effects of androgens and progestins on 1) HDL-mediated cholesterol efflux, a key cardioprotective function of HDL, 2) HDL-associated protein composition, and 3) adipose tissue inflammation, a critical mediator of insulin resistance. Emerging data implicates each of these in the pathogenesis of CVD and each is likely modified by exogenous steroids. We will conduct a placebo-controlled trial in healthy men to directly quantify the effects of increasing levels of serum testosterone alone or combine with an effective contraceptive progestin, depomedroxyprogessterone acetatate (DMPA), on human HDL and adipose tissue. To compliment our human study, we will use genetically modified mice to determine whether androgens reduce CVD risk via effects on adipose tissue macrophages, a central cell type in orchestrating adipose tissue inflammation and insulin resistance. The proposed studies will provide both clinical and mechanistic data regarding the impact of androgens and progestins on male metabolism and CVD risk.